Evaluation of a CCR5 Vaccine for HIV Infection in the SIV/Macaque Model. HIV vaccine development has been complicated by the extensive antigenic variation displayed by HIV. As an alternative to targeting the virus, we have developed vaccines targeting CCR5, a self- protein that is critically involved in HIV replication, transmission, and pathogenesis. By displaying peptides derived from CCR5 at high density on the surface of virus-like particles (VLPs), we have shown that we can efficiently overcome the mechanisms of B cell tolerance that normally limit the ability to induce high-titer IgG antibodies against self-proteins. Our VLP-based vaccines induce high- titer IgG antibodies against CCR5, these antibodies bind to native CCR5 and inhibit viral replication. In this project, we will evaluate the ability of a VLP-based vaccine targeting CCR5 to inhibit mucosal SIV infection of macaques. In Aim 1 we will evaluate the immunogenicity of our vaccines upon intramuscular and intravaginal inoculation. In Aim 2 we will challenge rhesus macaques via a vaginal challenge protocol and assess the protection provided by vaccination. These studies will allow us to assess the potential of vaccines targeting CCR5 to protect against HIV infection. PUBLIC HEALTH RELEVANCE: In this project, we will evaluate the ability of a VLP-based vaccine targeting the HIV receptor, CCR5, to prevent SIV infection in macaques.